Symptomatic COVID-19 Infections Lead To Impaired Pain Modulation In Young Adults

A new study by American researchers from the University of Florida and the University of Oklahoma has found that symptomatic COVID-19 infections lead to impaired pain modulation in young adults.

The study findings were published in the peer reviewed Journal of Pain.
https://www.jpain.org/article/S1526-5900(22)00359-5/fulltext

This study compared pressure pain sensitivity and pain modulatory function in individuals who have been previously infected by COVID-19, both symptomatically and asymptomatically, to a control group that did not have COVID-19. The primary findings of this study were

1) pressure pain sensitivity did not differ among groups,

2) the magnitude of exercise-induced hypoalgesia (EIH) was not different between groups, and

3) the conditioned pain modulation (CPM) response in symptomatic COVID-19 was significantly lower than the asymptomatic and control groups in the arm.

The magnitude of the CPM response in the arm was significantly lower in the symptomatic group than asymptomatic group and control group whereby the symptomatic COVID-19 group showed a lack of CPM response.

Pain sensitivity in both the upper and lower extremity in previously symptomatic COVID-19, asymptomatic COVID-19 and control groups showed no statistical difference. While we did expect to find a difference between groups, previous exposure to SARS-CoV-2 appeared to not have an effect on pressure pain sensitivity.

Our group was homogeneous and did not differ in mood 7, catastrophizing 16, and physical activity 17 which have all been reported as determinants that may affect pain sensitivity. Particpants that were tested did not have an active COVID-19 infection and it would be interesting to investigate whether an active COVID-19 case attenuates pressure pain responses.

Individuals who had symptomatic COVID-19 seemed to have a dysfunctional CPM response in a distal location; the forearm compared to the other two groups. The mean arm CPM response was -1% in the symptomatic group compared to the control group and the asymptomatic group whose pain thresholds increased following the cold pressor test by 33% and 26%, respectfully.

This magnitude is similar to the mean magnitude of CPM evoked (29%) in studies using healthy controls in a recent meta-analysis review 61. The included studies in the analysis used the CPT 15, 25, 37, 60, 64, 68, 74, 80, heat 25, 39, 57, 68, ischemia 9, 20, 21, 62, and chemical stimuli 2, 23, 26, 71 as the conditioning stimulus, with the most common being the CPT 61 similar to that used in the present study.

Our finding of an attenuated response in the symptomatic group is similar to those who have been diagnosed with chronic pain conditions such as fibromyalgia 34, 53, 58, 59, headache/migraine 10, 14, 54, 63, 73, arthritis 1, 35, 41, irritable bowel syndrome 83, 84 and myalgia 40 whereby the CPM response magnitude was significantly lower compared to the control groups. Impaired CPM predicts chronic post-operative pain when assessed in pain-free individuals prior to surgery 87 and has potential utility as a biomarker for chronic pain risk.

Pro-inflammatory cytokines can sensitize or activate nociceptors and transmit painful stimuli to the brain 89. The surface expressed angiotensin converting enzyme 2 (ACE2) has been found to be main receptor for uptake of SARS-CoV-2 spike protein 29. Evidence indicates that ACE2 expressing sensory neurons synapse with spinal and brainstem central nervous system (CNS) neurons leading to neurological effects, including headache and nerve pain 46, 48(17, 18).

Additionally activation of ACE2 receptors lead to an inflammatory response and a viral infection may cause localized and systematic inflammation. Inflammation is a key proponent of pain and impaired pain modulation, as such, could be a reason as to why pain modulation is impaired in those who have had symptomatic COVID-19 and may be experiencing lingering inflammation.

Despite our findings of differences in CPM among groups, we found no differences in the EIH response in individuals who have had symptomatic COVID-19 and those who did not. CPM and EIH have been shown to correlate 42, 77, however in younger adults, this relationship has not been consistently observed 56. Our sample, other than COVID-19 infection status, was relatively homogenous, especially in regards to age and PA, which are thought to play a role in EIH.

Endogenous opioids 32, hemodynamics 22, pro-inflammatory cytokines31, and distraction 19 have also been proposed as possible mechanisms underlying EIH. Our findings seem to indicate that COVID-19 infection does not seem to alter this pathway(s). This further highlights existing evidence 18 that CPM and EIH do not necessarily modulate pain sensitivity using the same shared pathways.

Furthermore, regular physical activity across all three groups may attribute to the groups not having an impaired EIH response following COVID-19 infection as exercise elicits an anti-inflammatory mechanism 24 that may sub serve as protection from the pro-inflammatory effects of COVID-19.

Similar to other pain conditions, there is broad inter-individual variability in both EIH and CPM but it is generally accepted that multiple factors affect pain modulation (see 52, 66 for review) and could be contributing to the high levels of variability of CPM and EIH response within our sample.

This study had several limitations to note. Firstly, individuals who previously had asymptomatic COVID-19 may not have had antibodies present. SARS-CoV-2 antibodies remain stable for at least 5 months after an infection with the virus 8, so participants who were in the control group may have had asymptomatic COVID-19 prior to the 5 months.

Second, we used recall for symptoms that the participants had when they had an active case of COVID-19. We did not assess whether or not they had long COVID-19, nor did we collect detailed information on current health status or current symptoms. At the time of testing (spring 2021), data on long-COVID was emerging and was not fully established, therefore additional studies assessing long COVID-19 symptoms and their impact on modulatory function is warranted.

While we collected data on the painfulness of the CPM protocol, we did not ask the participants to rate the pain of the EIH protocol. This would have been helpful to evaluate the endogenous pain-inhibitory effects of the exercise, as EIH magnitude can be influenced by the painfulness of the exercise. Time of day was not controlled for during PPT testing.

It has been suggested that time of day is a contributing factor to pain sensitivity; however, inconsistent findings have been found at which time participants were most sensitive to pain at its peak 4, 5. It is possible that this study was underpowered, however, since we did find a result with CPM and not the other two tested variables (EIH and pain sensitivity); it is possible that what we found regarding CPM is significant and concerning.

Despite these limitations, the current study adds COVID-19 infection to a growing list of conditions characterized by impaired pain modulation. The results from the study indicate CPM function was impaired in individuals who had symptomatic COVID-19. No differences between groups were found in pressure pain sensitivity, and no differences between symptomatic group and the other two groups were found in EIH.

CPM seemed to be effected by symptomatic COVID-19 with the EIH response remaining unaffected; the exact mechanisms of CPM and EIH need further exploration especially regarding conditions that involve acute systemic inflammation. Impaired CPM response could be an indication on whether or not COVID-19 exposure may have long-term implications on pain modulation and increased risk of chronic pain development. This study used younger adults who were not admitted into the ICU; additional research in older adults and those who had more severe symptoms of COVID-19 is warranted. Those who were admitted to the ICU with more severe symptoms may have different or more profound implications to pain modulatory function and this is very important to address due to the association between chronic pain and impaired pain modulation.
This study and its findings add to the growing body of literature that there are residual consequences of COVID-19. It is unknown whether CPM remains dysregulated long term and this should be addressed in future research studies, both cross sectional and longitudinal. CPM was impaired in individuals who had symptomatic COVID-19, which may have long-term implications on pain modulation. These findings are concerning in that normally healthy, young adults who have demonstrated only mild to moderate symptoms of COVID-19 have an impaired CPM response, as such, pain modulatory function should be examined in symptomatic COVID-19 older adults and in those vulnerable populations who are at risk for chronic pain development.